18-51065519-A-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP2 PP3_Strong

The NM_005359.6(SMAD4):c.1052A>T(p.Asp351Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D351N) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD4 NM_005359.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3
• Conservation: PhyloP100: 9.14

Genes affected

SMAD4 (HGNC:6770): (SMAD family member 4) This gene encodes a member of the Smad family of signal transduction proteins. Smad proteins are phosphorylated and activated by transmembrane serine-threonine receptor kinases in response to transforming growth factor (TGF)-beta signaling. The product of this gene forms homomeric complexes and heteromeric complexes with other activated Smad proteins, which then accumulate in the nucleus and regulate the transcription of target genes. This protein binds to DNA and recognizes an 8-bp palindromic sequence (GTCTAGAC) called the Smad-binding element (SBE). The protein acts as a tumor suppressor and inhibits epithelial cell proliferation. It may also have an inhibitory effect on tumors by reducing angiogenesis and increasing blood vessel hyperpermeability. The encoded protein is a crucial component of the bone morphogenetic protein signaling pathway. The Smad proteins are subject to complex regulation by post-translational modifications. Mutations or deletions in this gene have been shown to result in pancreatic cancer, juvenile polyposis syndrome, and hereditary hemorrhagic telangiectasia syndrome. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_005359.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-51065518-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 375998.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, SMAD4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD4	NM_005359.6	c.1052A>T	p.Asp351Val	missense_variant	9/12	ENST00000342988.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD4	ENST00000342988.8	c.1052A>T	p.Asp351Val	missense_variant	9/12	5	NM_005359.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2020

The p.D351V pathogenic mutation (also known as c.1052A>T), located in coding exon 8 of the SMAD4 gene, results from an A to T substitution at nucleotide position 1052. The aspartic acid at codon 351 is replaced by valine, an amino acid with highly dissimilar properties. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one individual with Juvenile Polyposis syndrome (JPS) (Ambry internal data). This variant has also been observed in individuals who have a personal or family history that is consistent with JPS (Ambry internal data). The same amino acid change has been reported in an individual with overlapping features of JPS and hereditary hemorrhagic telangiectasia (HTT) (Bishop JC et al. J Pediatr Genet, 2018 Jun;7:78-82). A different alteration in the same codon (p.D351H) has been observed in an individual with HTT (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 28, 2018

Variant summary: SMAD4 c.1052A>T (p.Asp351Val) results in a non-conservative amino acid change located in the dwarfin-type domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 121412 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1052A>T has been reported in the literature in an individual with colorectal cancer (Adua 2017) and Juvenile Polyposis (Bishop 2017), however neither report provides strong evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

SMAD4-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 09, 2024

The SMAD4 c.1052A>T variant is predicted to result in the amino acid substitution p.Asp351Val. This variant was reported in an individual with juvenile idiopathic arthritis with combined JP-HHT syndrome (Bishop et al. 2018. PubMed ID: 29707409) and in a tumor sample from an individual with colorectal cancer (Adua et al. 2017. PubMed ID: 28685087). This variant has not been reported in a large population database, indicating this variant is rare. It has conflicting interpretations of uncertain and pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/405499/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Juvenile polyposis syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 21, 2016

This sequence change replaces aspartic acid with valine at codon 351 of the SMAD4 protein (p.Asp351Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a SMAD4-related disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	32
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	1.0	D;D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H;H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-8.8	D;D;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.99
MutPred		0.85		Loss of phosphorylation at Y353 (P = 0.0814);Loss of phosphorylation at Y353 (P = 0.0814);.;
MVP		0.99
MPC		3.5
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.96
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1060500741; hg19: chr18-48591889; COSMIC: COSV61693805; COSMIC: COSV61693805;